ABSTRACT Hypertension is more prevalent in men compared to premenopausal women, but this relationship is reversed as women progress towards menopause. Although gonadal hormones have been investigated as a source of sex differences in blood pressure, the role of estrogen signaling in hypertension and cardiovascular disease and the potential benefits of estrogen-based therapeutic strategies are controversial. This deficiency may be attributed to clinical study of older women with pre-existing cardiovascular and other health conditions. Compounding this ambiguity, our understanding of the basic biological mechanisms that may contribute to hypertension associated with gonadal decline has been obscured by the use of preclinical models reliant on the use of ovariectomized or aged animal animals. In the parent R01, we have utilized a strategy involving a rodent model of accelerated ovarian failure (AOF) induced by 4-vinylcyclohexene diepoxide (VCD) that recapitulates the stages of human menopause, including a peri-AOF stage comparable to perimenopause, in non-aged animals. This approach has been integrated into a multidisciplinary strategy to test the central hypothesis that estrogen receptor (ER?) influences the susceptibility to hypertension and glutamate receptor plasticity in the paraventricular hypothalamic nucleus (PVN), a key central coordinator of sympathetic output that is linked to the emergence of hypertension in females. Significantly, hypertension is an important risk factor for cognitive decline and dementias, including Alzheimer's disease (AD). As with hypertension, there is a significant sex divergence in the susceptibility to AD, and the potential benefits of estrogen replacement therapies in AD treatment are controversial. In this supplement, we propose to incorporate both dementia-associated brain pathology and cognitive dysfunction as endpoints to our study of peri-AOF hypertension. We will test the hypothesis that AOF will exacerbate amyloid-associated neural pathology in the hippocampus and cognitive impairment in female amyloid precursor protein (APP) mutant mice (Tg-5xFAD; TgSwDI). This supplement has the potential to significantly expand our lab's current study of menopausal hypertension, and provide important pilot data for further exploration of the linkages between gonadal hormones, hypertension, and the plasticity or pathology of brain function associated with beta-amyloid aggregation.